Water soluble entrapping of a drug

ABSTRACT

MATERIALS ARE ENTRAPPED IN WATER SOLUBLE HYDROXYALKYL ACRYLATE OR METHACRYLATE POLYMERS TO PROVIDE READY SOURCES OF THE MATERIAL BY THE DELETION OF WATER. THUS, THERE CAN BE ENTRAPPED DRUGS, PESTICIDES, FLAVORING AGENTS AND FRAGRANCES.

United States Patent 3,660,563 WATER SOLUBLE ENTRAPPING OF A DRUGFrancis E. Gould, Princeton, and Thomas H. Shepherd,

Hopewell, N.J., assignors to National Patent Development Corporation,New York, N.Y.

No Drawing. Continuation-impart of applications Ser. No. 567,856, July26, 1966, now Patent No. 3,520,949, Ser. No. 650,259, June 30, 1967, andSer. No. 654,044, July 5, 1967. This application is also a division ofapplication Ser. No. 833,182, June 13, 1969, now Patent No. 3,576,760.This application Sept. 9, 1970, Ser.

Int. Cl. A61k 9/00 US. Cl. 424-81 4 Claims ABSTRACT OF THE DISCLOSUREMaterials are entrapped in water soluble hydroxyalkyl acrylate ormethacrylate polymers to provide ready sources of the material by thedeletion of Water. Thus, there can be entrapped drugs, pesticides,flavoring agents and fragrances.

This application is a continuation-in-part of application 567,856 filedJuly 26, 1966, now Pat. 3,520,949 granted July 21, 1970, application650,259 filed June 30, 1967 and now abandoned, and application 654,044filed July 5, 1967; and is a division of application 833,182, filed June13, 1969 and now Pat. 3,576,760 granted Apr. 27, 21971.

The present invention relates to the preparation of ingredientsentrapped in a water soluble polymer.

'Linear hydroxyalkyl acrylate and methacrylate soluble in solvents otherthan water are disclosed in our copending application Ser. No. 654,044,filed July 5, 1967. These polymers, however, are not soluble in water asthe sole solvent.

Frequently it is desirable, however, to entrap materials in a watersoluble polymer, Thus, the advantages of a Water soluble polymer becomeapparent in certain uses, e.g., in the entrapment of flavors, perfumes,etc. wherein the polymer carrying the entrapped material is added towater, as for example in a soft drink or in a detergent composition. Inthese cases it is desirable to have the polymer dissolve to avoid thepresence of suspended granules which can detract from the appearance ina drink or leave a dusty residue on clothing, dishes, etc. in the caseof a detergent.

The water soluble polymers also are advantageous in trapping certainspecies such as enzymes which will not tolerate alcohol or solventsother than water.

It is an object of the present invention to prepare novel compositionscontaining materials entrapped in a water soluble polymer.

Another object is to protect materials from attack by atmosphericoxygen.

A further object is to devise a means for contacting non-water solublematerials with an aqueous environment.

Still further objects and the entire scope of applicability of thepresent invention will become apparent from the detailed descriptiongiven hereinafter; it should be understood, however, that the detaileddescription and specific example, while indicating preferred embodimentsof the invention, are given by way of illustration only, since variouschanges and modifications Within the spirit and scope of the inventionwill become apparent to those skilled in the art from this detaileddescription.

It has now been found that these objects can be attained by employingwater soluble hydrophilic poly- 3,660,563 Patented May 2, 1972 mers ofhydroxyalkyl acrylates and methacrylates as entrapping agents. Thusthere are employed copolymers of hydroxyethyl acrylate, hydroxypropylacrylate, hydroxyethyl methacrylate or hydroxypropyl methacrylate with0.5 to 20% of a water solubilizing copolymerizable monomer. Thecopolymerizable monomer should be present in amount sufiicient to besure that the polymer is completely soluble in water. Of course,mixtures of hydroxyalkyl acrylates and methacrylates can be employed.Thus, while the hydroxyalkyl methacrylate esters are preferred asstarting material up to about 40% by weight of hydroxyalkyl acrylate canbe used in the hydroalkyl methacrylate containing mixture of monomers.

The polymers employed in the present invention being water solubledistinguish not only from those in our prior application but alsodistinguish from the cross linked hydroxyalkyl methacrylate polymers andthe like shown in Wichterle Pat. 3,220,960 for example, since theWichterle polymers is not soluble in any solvent, but only swellable.The polymers employed in the present invention are not only soluble inwater but are also soluble in many polar solvents.

The polymers employed in the present invention have the advantage overconventional water soluble polymers such as polyethylene oxides,polyvinyl alcohol, cellulose ethers, etc. in the barrier properties ofthe dry polymer. The polymers of the present invention give superiorprotection to entrapped species from atmospheric oxygen and are superiorin preventing difiusion and loss of the entrapped species.

The solubilizing comonomer in polymerizing the hydroxyalkyl acrylate ormethacrylate can be either (1) an ammonium or alkali metal (e.g., sodiumor potassium) salt of a polymerizable ethylenically unsaturated (ornonbenzenoid unsaturated) organic acid or (2) a strong acid salt of apolymerizable ethylenically unsaturated (or nonbenzenoid unsaturated)amino containing monomer.

Examples of organic acids for making the ammonium and alkali metal saltsinclude acrylic acid, methacrylic acid, maleic acid, fumaric acid,itaconic acid, aconitic acid, cinnamic acid, crotonic acid, cyclohexene,carboxylic acid, propiolic acid, mesaconic acid, citraconic acid, vinylsulfonic acid, p-vinylbenzenesulfonic acid, partial esters such as mono2-hydroxyethyl citraconate, mono 2- hydroxypropyl itaconate, mono2-hydroxyethyl itaconate, mono 2-hydroxypropyl citraconate, mono2-hydroxyethyl maleate, mono 2-hydroxypropyl fumarate, mono methylitaconate, monoethyl itaconate, mono methyl Cellosolve itaconate (methylCellosolve is the monomethyl ether of diethylene glycol), mono methylCellosolve maleate, mono-2-hydroxyethy1 aconitate.

Examples of strong acid salts of polymerizable amino containing monomersare the hydrochloric, hydrobromic, sulfuric acid, nitric acid,phosphonic acid, benzene sulfonic acid, naphthalene sulfonic acid,trichloroacetic acid, and p-toluene sulfonic acid salts ofdiethylaminoethyl methacrylate, dimethyl aminoethyl methacrylate,monomethylaminoethyl methacrylate, t-butylarninoethyl methacrylate, paminostyrene, oaminostyrene, 2-amino-4- vinyltoluene, diethylaminoethylacrylate, dimethylaminoethyl acrylate, t-butylaminoethyl acrylate,piperidinoethyl acrylate, piperidinoethyl methacrylate, morpholinoethylacrylate, morpolinoethyl methacrylate, 2-viny1 pyridine, 3-viny1pyridine, 4-vinyl pyridine, 2-ethyl-5-vinyl pyridine,dimethylaminopropyl acrylate, dimethylamino propyl methacrylate,dipropylaminoethyl acrylate, dimethylaminoethyl vinyl ether,dimethylaminoethyl vinyl sulfide, diethylaminoethyl vinyl ether,aminoethyl vinyl ether, 2- pyrrolidinoethyl methacrylate,3-(dimethylaminoethyl)- 2-hydroxypropyl acrylate,3-(dimethylaminoethyl)-2-hydroxypropyl methacrylate, 2-aminoethylacrylate, 2-

aminoethyl methacrylate. The alkylaminoethyl acrylates and methacrylatesare preferred ingroup (2).

A portion (up to 40% of total monomers) of the hydroal'kyl acrylate ormethacrylate can be replaced by acrylamide, methacrylamide, n-isopropylmethacrylamide, n-methylacrylamide, n-methyl methacrylamide,n-12-hydroxyethyl, acrylamide, n-(Z-hydroxyethyl methacrylamide).

When materials which are not water soluble are desired to be entrappedthis can be accomplished providing they are soluble in other solvents inwhich the copolymers of the present invention are soluble. Such solventsinclude methanol, ethanol, isopropanol, n-propanol, methyl Cellosolve(monomethyl ether of diethylene glycol), ethyl Cellosolve, monoethylether of 'diethylene glycol, dioxene-water mixtures, pyridine, dimethylformamide, dimethyl sulfoxide, tetrahydrofurfuryl alcohol and mixturesof any of the above-mentioned solvents with each other or water.

On contact of such water insoluble entrapped materials with water, thepolymer dissolves, leaving the entrapped species exposed and in contactwith the aqueous environment. This can be taken advantage of in applyingpesticides to the soil. For example, the entrapped pesticide can beapplied in the dry form to the top of the soil or it can be embedded inthe soil and will be released as a result of rain or artificialWatering.

Usually 0.1 to 35% of the entrapped material is employed based on theweight of the polymer.

The water soluble polymers of the present invention are infinitelysolube in water, although at concentrations above 30% solution viscosityrises sharply.

Solubility of the polymers is pH dependent. For example, polymerscontaining salts of carboxylic or sulfonic acids as part of thestructure will not be soluble at a pH below about 3.5 and polymerscontaining amine salts as part of the structure will not be soluble at apH above about 8.5.

Thus, for release of fragrance in common alkaline detergents, e.g.,soap, sodium decylbenzene sulfonate, sodium lauryl sulfate, sodiumdodecylbenzene sulfonate, sodium propyl naphthalene sulfonate, sodiumdi(Z-ethylhexyl) sulfosuccinate, sodium alkyl benzene sulfonates having14 to 18 carbon atoms in the alkyl group or the like (i.e., anionicdetergents) polymers containing carboxylate salt groups are primarilyuseful whereas for cationic detergents, e.g., trimethylbenzylammoniumchloride, l-lauryl-3-ethylbenzotriazolium bromide, trimethylstearamidoethyl ammonium sulfate and lauryl trimethyl ammonium chloride.Those polymers containing amine salt groups are preferable. Either typeof polymer can be used with equal facility with non-ionic detergentssuch as p-isooctylphenol condensed with ethylene oxide units,polyoxyethylene 'sorbitan monooleate tertiary dodecyl polyethyleneglycol thioether, tri(poloxyethylene sorbitan monopalmitate), Spans,Tweens, etc., providing there is not present another ingredient whichcauses a substantial pH shift away from percent.

Any common fragrance or food flavor can be entrapped, e.g. orange oil,citral, coffee, tea, lemon oil, synthetic lemon-lime flavor, strawberryflavor, vanilla, biacetyl, anise, lilac fragrance, pine fragrance,peppermint oil, oil of orchids essence, anethole, ethyl propionate,ethyl acetate, acetaldehyde, menthol and Spearmint.

In addition to fragrances and food flavors, there can be entrapped inthe water soluble polymers pesticides including bactericides,fungicides, insecticides and nematocides, enzymes and drugs.

Examples of bactericides include trimethyl benzyl ammoniurn chloride,cetyl pyridinium chloride, hexachlorophene, streptomycin, salicylicacid, penicillin, aureomycin, chloromycetin, merthiolate, sulfanilamide,sulfathiazole,

fungicides including methyl-l-(butylcarbamoyl)-2-benzimidazolecarbamate, N-trichloromethylthio-4-cyclohexene 1,2-dicarboximide, methylmercury, 2,3-dihydroxypro- 4 pyl mercaptide, methyl mercury acetate,N-(ethylmercury)-p-toluenesulfonanilide, chloranil, l,4dichloro-2,5-dimethoxybenzene, copper carbonate, copper oleate, basic cupricchloride, cuprous oxides 3-[2-(3,5-dimethyl-2-oxocyclohexyl) 2hydroxyethyl] glutarimide, 2,4,5,6-tetrachloroisophthalonitrile,tetrahydro-3,5-dimethyl-2H-3,5- thiadiazine-Z-thione,2,6-dichloro-4-nitroaniline, p-dimethylaminobenzenediazo sodiumsulfonate, bis(n-propylsulfonyl) ethylene (B1843),2,3-dichloro-1,4-napthoquinone, cis N-[l,1,2,2-tetrachloroethyl)thio]-4-cyclohexene-l,2- dicarboximide,coordination product of zinc and manganese ethylene bisdithiocarbamate(Dithane M-45), mixture of nickel sulfate and manganous ethylene bis[dithiocarbamate (Dithane S-3l), dodecylguanidine acetate, 2,4-dichloro-6-(o-chloroanilino)-s-triazine, sodiumethylmercurithiosalicylate, 3,4,5,6,7,7 hexachloro-N-(ethyl mercuri)1,2,3,6 tetrahydro-3,6-endo-methanophthalimide, ferric dimethyldithiocarbamate, N-(trichloro-methylthio) phthalimide,Z-heptadecyl-imidazoline acetate, Griseofulvin, hexachlorobenzene,1-chloro-2-nitropropane, manganous ethylene bis carbamate,3,4,5,6,7,7-hexachloro-N- (methylmercuri) -1,2,3,6-tetrahydro-3,6-endo-methanophthalimide, mercuric chloride, sodiummethyldithiocarbamate, 6-methyl-2,3-quinoxalinedithiol cyclic-S,S-dithiocarbonate (also mites) disodium ethylenebisdithiocarbamate, manganesedimethyl dithiocarbamate and mercaptobenzothiazole mixture, (Niacide),methyl mercury 8-hydroxyquinoline, 2-phenylphenol, methyl mercurydicyandiamide, phenylmercuritriethanolammonium lactate,pentachloronitro-benzene, phenylmercury urea, 3-(2-methylpiperidino)propyl 3,4-dichlorobenzoate, 2,3-dihydro-5-carboxanilido-dmethyl-1,4-oxathin-4 dioxide, phenylmercuric acetate,Polyram, 8-hydroxyquinoline sulfate, hydroxymercuri-nitrophenol andhydroxymercurichlorophen01 mixture, sulfur,5-ethoxy-3-trichloromethyl-1,2,4-thiadiazole,1,2,4,S-tetrachloro-3,nitrobenzene, bis (dimethylthiocarbamoyl)disulfide, 3,5,6-trichloro-o-anisicacid, triphenyltin hydroxide,2,3-dihydro-5-carboxanilido-6-methyl-l,4-oxathiin, zinc ethylenebisdithiocarbamate, zinc dimethyl dithiocarbamate and laurylisoquinolium bromide. Insecticides (or miticides) including,0,0,0',O'-tetramethyl 0,0-thiodi-p-phenylene phosphorothioate, isopropyl4,4'-dichloro-benzilate, O-[Z-chloro l-(2,5-dichlorophenyl)-vinyl]0,0-diethyl phosphorothioate, aldrin, allethrin, 0,0,0,0-tetrapropyldithiopyrophosphate, 0,0-diethyl-S- [f1 oxo-1,2,3-benzotriazin-3-(4H)-ylmethyl]-phosphorodithioate, 0,0 dimethyl s[4-oxo-1,2,3-benzotriazin-3 (4H) ylmethyl] phosphorodithioate, dimethylphosphate of 3 hydroxy N methyl cis crot-onamide, 2 isopropoxyphenyl Nmethyl carbamate, benzene hexachloride (BHC), dimethyl phosphate of 3hydroxy-N,N-dimethyl-cis-crotonamide, 2-sec-butyl4,6-dinitrophenyl-3-methyl-2-butenoate, dimethyl 3-hydroxyglutaconatedimethyl phosphate, dimethyl (2,2,2-trichloro-1- hydroxyethyl)phosphorate ester of butyric acid, m-(lmethyl-butyl) phenylmethylcarbamate, -m(1-ethylpropyl) phenyl methyl carbamate, calcium cyanide,l-naphthyl N- methylcarbate, 2,3 dihydro-Z,2-dimethyl-7-benzofuranylmethyl carbamate, S-[(p-chlorophenylthio)methyl]0,0- diethylphosphorodithioate, m[ (dimethylamino)methylene]amino]phenylmethylcarbamate hydrochloride, chlordane, ethyl 4,4-dichlorobenzilate,N,N-dimethyl-N'-(2- methyl-4chlorophenyl)-formamidine, dimethylphosphate of a-methylbenzyl 3-hydroxy-cis-crotonate,0,0-diethyl-O- 3chloro 4-methyl-2-oxo-2H-l-benzopyran-7-ryl-phosphorothioate, cyclicethylene (diethoxyphosphinyl) dithiomido carbonate,1,1-dichloro-2,2-bis(p-chlorophenyl) ethane, DDT(1,1,1-!trichloro-2,2-bis (p-chlorophenyl) ethane, Demeton (mixture of0,0-diethyl-O-[2-(ethylthio)ethyl] phosphorothioate and0,0-diethyl-S-[2-ethylthio)ethyl]phosphorothioate),0,0 dimethylO-(2,2-dichlorovinyl phosphate (DDVP), 0,0-diethylO-(2-isopropyl-(o-methyl-4-pyrimidyl) phosphorothioate, O-2-chloro-4-nitropheny1 0,0-diethy1 phosphorothioate, Dieldrin, 2-

nitro-l,l-bis(p-chlorophenyl) butane, 2-nitro-1,l-bis-(pchlorophenyl)propane, tetramethyl phosphorodiamidic fluoride, 2,4-dimethylbenzyl2,2-dimethyl-3-(2-methyl propenyl) cyclopropanecarboxylate,4,4'-dichloro-a-methylbenzhydrol (primarily an acarcicide and miticide),4,6-dinitro o cyclohexylphenol, 2sec-butyl-4,6-dinitrophenyl isopropylcarbonate (miticide), 2,3-p-dioxanedithiol-S,S- bis(0,0-diethylphosphoro-dithioate), diphenylamine, 0,0diethyl-S-[Z-(ethylthio)-ethyl]phosphorodithioate,0,0-diethyl-O-(3,5,6-trichloro-2-pyridyl) phosphorothioate,O-ethyl-S-phenyl-ethylphosphonodithioate 6,7,8,9,10, 10hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3-benzodioxathiepin-3 oxide, Endrin, O-ethyl-O-p-nitrophenylphenylphosphonothioate, 2,3-quinoxaline-dithiol cyclic trithiocarbamate(ovicide for spider mites), 0,0, O',O'-tetraethyl S,S'-methylenebiophosphorodithioate (mites), 0,0-dimethyl-O- [4-methylthio -m-tolyl]-phosphorothioate, 2-chloro-1-(2,4,5-trichlorophenyl) vinyl dimethylphosphate, 2,4-dichlorophenyl ester of benzene sulfonic acid,Heptachlor, hydroxymercurichlorophenol, N- (mercaptomethyl) phthalimideS-(0,0-dimethyl phosphorodithioate), 2- l-methylheptyl)4,6-dinitrophenyl crotonate,decachloroootahydro-1,3,4-metheno-2H-cyclobuta[cd]pentalen-2-one,2,3,5-trimethylphenylcarbamate, 3,4,5-trimethylphenyl carbamate, dibasic lead arsenate,flbutoxy-B'-thiocyanodiethyl ether, 1,2,3,4,5,6-hexachloro cyclohexanegamma isomers 5,6-dichloro-2-trifiuoromethylbenzimidazole-l-carboxylate(mites), 0,0-dimethyl phosphoro-dithioate of diethyl mercaptosuccinate,4-(dimethylamino)-m-tolyl methylcarbamate, 0,0-diethyl-S- (Nethoxycarbonyl N-methyl-carbamoylmethyl) phosphorothiolothionate, S-(4,6-diamino-s-triazin-2-ylmethyl) 0,0-dimethyl phosphorodithioate,4-(methylthio)-3,5-tylylmethylcarbamate, S methyl N-[ (methylcarbamoyl)-oxy] thioacetamidate, 2,2-bis(p-methoxyphenyl-1,1,l-trichloroethane(Methoxychlor), bromomethane, -[2- Eethylthio)ethyl] 0,0-dimethylphosphorothioate (Meta Systox), 0,0-dimethyl-O-p-nitrophenylphosphorothioate, S-[[(p-chlorophenyl)thioJmethyl] 0,0-dimethylphosphorodithioate, 3-(p-bromophenyl)-1-methoxy-l-methylurea,Z-carbomethoxy-l-methylvinyl dimethyl phosphate (ix-isomer,4-benzothienyl N-methyl carbamate, O,S-dimethyl phosphoramidi-thioate,1,2-dibromo-2,2-dichloroethyl dimethyl phosphate, naphthalene,2,2-dimethyl-3-(2- methylpropenyl) cyclopropaneearboxylic ester ofN-(hydroxymethyl)-l-cyclohexene-1,2-dicarboximide, nicotine (3(1-methyl=2-pyrrolidyl)pyridine),o-dichlorobenzene,p-chlorophenyl-p-chlorobenzenesulfonate (mites), p-di chlorobenzene,0,0-diethyl-O-p-nitr0-phenyl phosphorothioate (Parathion), coppermeta-arsenite copper acetate complex (Paris green),decachlorobis(2,4-cyclopentadienel-yl) (mites),l,1-dichloro-2,2-bis(p-ethylphenyl)ethane, dibenzo 1,4 thiazine,0,0-diethyl 'S-(ethylthio)-methyl phosphorodithioate,2-chloro-Z-diethylcarbamoyl-l-methylvinyl dimethyl phosphate, Piperonylbutoxide, O-ethyl S,S-dipropyl phosphorodithioate, pyrethrins,0,0-dimethyl-O-(2,4,5-trichlorophenyl) phosphorothioate, rotenone,4t-butyl-2-chlorophenyl O-methyl methylphosphoroamidate, ryanodine,sabadilla, (S-benzyl-S-furyl) methyl-2,2- dimethyl-3- Z-methylpropenyl)-cyclopropanecarboxylate, ootamethylpyrophosphoramide, sodium fluoride,6 (and 2)- chloro-3,4-xylylmethylcarbate, polychlorinated (66% Cl)terpene, p-chlorophenyl phenyl sulfone (mites), 0,0- dimethylO-(4-nitro-m-tolyl)-phosphorothioate, Z-methyl- Z-(methylthio)propionaladehyde O-(methylcarbamoyl) oxime, tetraethyl pyrophosphate, 4chlorophenyl 2,4,5- trichlorophenyl sulfone, isobornyl thiocyanoacetate,chlorinated (67-69%) camphene, 0,0-dimethyl(2,2,2-trichloro-l-hydroxyethyl) phosphonate and 0,0-diethyl-O-(2-pyrozinyl) phosphorothioate.

Herbicides including 2 (ethylamino) 4 (isopropylamino)-6-(methylthio)-s-triazine, 3 amino-2,5-dichlorobenzoic acid,3-amino-l,2,4-triazole, ammonium sulfamate, 2-triazine,Z-chloro-4-ethylamino-6-isopropylaminos-triazine,polychlorobicyclopentadiene, 4-chloro-2-butynyl-m-chlorocarbanitate, Nbutyl-N-ethyl-a,a,a-trifluoro- 2,6-dinitro-p-toluidine, S(0,0-diisopropyl phosphorodithioate) ester of N-(Z-mercaptoethyl)benzenesulfamide, methyl m-hydroxycarbanilate, m-methyl carbanilate,3,5- dibromo-4-hydroxybenzonitrile, S-ethyl diisobutylthiocarbamate, N,Ndiallyl 2 chloroacetamide, 2 chloroallyl diethyldithiocarbamate, 3[p-(p-chlorophen0xy)phenyl] l,l-dimethylurea, isopropylm-chlorocarbanilate, calcium methanearsonate, p-chlorophenoxy aceticacid, S-ethyl N-ethyl-N-cyclohexylthiocarbamate, 3',4dichlorocyclopropanecarboxanilide, 2,4-dichlorophenoxy acetic acid andits salts, e.g. butylamine salt, and esters, e.g. isooctyl ester,2,4,5-trichlorophenoxy acetic acid and its salts and esters,2,2-dichloropropionic acid, 4-(2,4-dichl0rophen0xybutyric acid itssalts, amine salts and esters, dimethyl- 2,3,5,G-tetrachlorophthalate,1,3-bis(1-hydroxy 2,2,2-trichloroethyl) urea, tris[(2,4-dichlorophen0xy)ethy1] phosphite, S 2,3 dichloroallyldiisopropylthiocarbamate, 3,6 dichloro-o-anisic acid, 2,6dichlorobenzo-nitrile, 2- (2,4-dichlorophenoxy) propionic acid,N,N-dimethyl-2,2- diphenylacetamide, diphenyl-acetonitrile,3-(3,4-dichlorophenyl)-1,l-dimethylurea, 2-methyl-4,6-dinitrophenolsodium salt, disodium methanearsonate, ethylene glycolbis(trichloroacetate), 7-oxabicyclo (2,2,1) heptane-2,3-dicarboxylicacid, -S ethyl dipropylthiocarbamate, 2-(2,4,5 trichlorophenoxy) ethyl2,2-dichloropropionate, diethyl dithiobis(thionoformate),2,3,6-trichlorophenylacetic acid or sodium salt,3-phenyl-1,l-dimethylurea, 3-phenyl-1,]- dimethylurea trichloroacetate,1,1-dimethyl-3-(a,a,a-trifiuoro-m-tolyl) urea, 2 t butylamino 4ethylamino-6 methylthio-s-triazine, 3,5-diiodo 4 hydroxybenzonitrile,hexachloroacetone, S-bromo 3 sec-butyl-6-methyluracil, potassiumcyanate, 2-chloro 2,6' diethyl-N-(methoxymethyl) acetanilide,3-cyclohexyl-6,7-dihydro-lH-cyclopentapyrimidine-2,4 3H,5H -dione, 3-3,4-dichlorophenyl)-l-methoxy-l-methylurea, 3(4-bromo-3-chlorophenyl)-l-methoxy-l-methylurea, mono ammonium methylarsenate, 2 methyl 4 chlorophenoxyacetic acid and its salts and esters,4-(2-methyl-4-chlorophcnoxy) butyric acid and its salts and esters, 2-(2-methyl-4-chlor0- phenoxy) propionic acid and its salts and esters,1,2- dihydro 3,6-pyridazinedione, S-ethyl heXahydro-lH-azepine 1carbothioate, 3 (p-chlorophenyl)-1,1-dimethylurea,3-(4-chlorophenyl)-1,l-dimethylurea trichloroacetate, 2,4bis[(3-methoxypropyl)-amino]-6-methylthio-striazine, monosodium acidmethanearsonate, N-l-naphthylphthalamic acid, l-butyl 33,4-dich1oropheny1)-lmethylurea, ethyl hydrogen l-propyl phosphonate, 4-(methylsulfonyl)-2,6-dinitro-N,N-dipropylaniline, 2,4-dichlorophenyl pnitrophenyl ether, 3 (hexahydro 4,7- methanoinden-S-yl)-1,1dimethylurea1,1'-dimethyl 4,4- bipyridinium dichloride or the corresponding bis(methyl sulfate), dimethylamine salt of polychlorobenzoic acid (PBA),pentachlorophenol, S-propyl butylethylthiocarbamate,4-amino-3,5,6-trichloropicotinic acid, 2,4'-dinitro-4-trifluoromethyldiphenyl ether, 2,4-bis(isopropylamino)-6-methoxy-s-triazine, 2,4 bis(isopropylamino) -6-methylthio)-s-triazine,2-chloro-N-isopropylacetanilide, 3,4-dichloropropionanilide,2-chloro-4,6-bis (isopropylamino -striazine, isopropylN-phenylcarbamate, 5-amin0-4-ch1oro- 2-phenyl-3(2H)-pyridazinone, sodium2 (2,4 dichlorophenoXy)-ethyl sulfate,1-(Z-methylcyclohexyl)-3-phenylurea, 2-(2,4,5-trichlorophenoxy)propionic acid and its salts and esters,2-chl0ro-4,6-bis(ethylamino)-s-triazine, sodium arsenite, sodiumchlorate, 3-chloro-2-methyl-pvalerotoluidine, m-(3,3-dirnethylureido)phenyl t-butyl carbamate, dimethylamine salt of 2,3,6-trichlorobenzoicacid, 2,3,6 -trichlorobenzyloxypropanol, trichloroacetic acid,trichlorobenzyl chloride, 3-t-butyl-5-chloro-6-methyluracil,2,6-di-t-butyl p tolylmethylcarbarnate, S-2,3,3-trichloroallyl-diisopropyl thiolcarbamate, a,a,a-trifluoro--2,6-dinitro-N,N-dipropyl-p-toluidine and S-propyldipropylthiolcarbamate.

Nematocides including chloropicrin (trichloronitromethane), 0,0-diethylO[p-methylsulfinyl)phenyl] phosphorothioate,1,2-dibrorno-3-chloropropane, D-D (mixture of 1,3-dichloropropene,3,3-dichloropropene, 1,2-dichloropropane and 2,3-dichloropropene),1,2-dibromo ethane, O 2,4 dichlorophenyl 0,0 diethyl phosphorothioate,3-bromo-1-propyne and tetrachlorothiophene. Defoliants and desiccantssuch as arsenic acid, dimethyl arsinic acid, calcium cyanimide,S,S,S-tributyl phosphorotrithioate, 4,6-nitrophenol-O-sec. butylphenol,6,7-dihydrodipyrido [1,2a;-2',1c] pyrazinedium salts, S,S,S-tributylphosphorotrithioite and magnesium chlorate; snail and lamprey controls,e.g. 2,5'-dichloro-4-nitrosalicylanilide.

Enzymes such as leucylpeptidase, aminopolypeptidase, fl-amylase,carboxypeptidase, pepsin, trypsin, luciferase, damino acid oxidase,phosphorylase, papain, catalase, ascorbic acid oxidase, malt diastase,rennin, pancreatin, aamylase, pectinase, lipase, phosphatase, pectase,urease, arginase and glyoxalase.

Unless otherwise indicated, all parts and percentages are by weight.

EXAMPLE 1 Into a 30-gallon reactor was charged 40 lbs. of hydroxyethylmethacrylate, 4 lbs. of methacrylic acid, 120 lbs. of methanol and 0.05lb. of t-butyl peroctoate. The reactor was heated to 80 C. and allowedto stir 6 hrs. to effect polymerization. To the polymer solution thusobtained was added 2.5 lbs. of sodium methoxide dissolved in 25 lbs. ofmethanol. The resulting solution was added slowly to a 10-fold excess ofacetone to precipitate the polymer. After drying, a yield of 36 lbs. ofwater soluble polymer was obtained.

EXAMPLE 2 The polymer of Example 1 was dissolved in methanol to providea 10 weight percent solution. To the solution was added orange oil at alevel of 20% of the polymer content of the solution. The solution wasthen cast as a 20 mil film (wet) on a polyethylene sheet and dried. Theresulting brittle film was ground to 60 mesh to yield a powder whichexhibited only a slight odor of orange oil, but which released orangeoil readily on contact with water.

EXAMPLE 3 The orange oil containing powder of Example 2 was blended witha commercial detergent (sodium dodecylbenzene sulfonate) at a level ofof the detergent. When the detergent was added to hot Water, the orangeoil odor was immediately apparent.

EXAMPLE 4 Example 2 was repeated using citral in place of orange oil. Adetergent composition prepared with citral containing polymer inaccordance with Example 3, immediately gave otf a citrus like odor whenadded to hot water.

EXAMPLE 5 The citral-containing polymer of Example 4 (without detergentswas pulverized to 325 mesh in a hammer mill. The micropulverized powderwas milled with a saponified coconut oil soap "base at a level of 1 1b.of powder to 9 lbs. of the soap. The soap was extruded and stamped intocakes. On use of the soap cake for hand washing, the citral odor wasevident on the hands. This eifect persisted through the life of the soapcake.

EXAMPLE 6 Example 1 was repeated with the exception that 1180 g. ofpotassium hydroxide dissolved in 2 gallons of water was employed forneutralization.

8 EXAMPLE 7 Examples 2-5 were repeated using, however, the polymer ofExample 6. Equivalent results were obtained.

EXAMPLE 8 Into a 30-gallon reactor was charged 40 lbs. of hydroxyethylmethacrylate, 1 lb. of methacrylic acid, 120 lbs. of methanol and 0.05lb. of t-butyl peroctoate. The reactor was heated to 85 C. and allowedto stir 5 hours to efiect polymerization. The polymer was isolated byprecipitation from the alcohol solution with water, and allowed to dry.A yield of 37 lbs. was obtained. The polymer was re-dissolved inmethanol to provide a 10 weight percent solution. To the solution wasadded 1 liter of 10% ammonium hydroxide, and the solution wasspray-dried to provide a water soluble powder suitable for entrapment offlavors, fragrances, drugs, pesticides, etc., of the types set forthabove, e.-g., using 10% of additive with the copolymer.

EXAMPLE 9 Strong coifee was brewed by slurrying g. of ground coifee in75 cc. of water and heating to the boiling point. The coflFee solutionwas filtered from the grounds, and 2 g. of the polymer of Example 8 wasdissolved in the solution. The solution was then evaporated to drynessin a rotary vacuum apparatus to yield a brittle film which was finelyground. On addition of the powder to boiling water, a beverage wasobtained which more nearly retained the flavor of fresh percolatedcoffee than the usual commercial instan cofiee.

EXAMPLE 10 Into a -gallon reactor was charged lbs. of hydroxyethylmethacrylate, 3 lbs. of dimethylaminoethyl methacrylate, 120 lbs. ofmethanol and 0.05 lb. of diisopropyl percarbonate. The reactor washeated to C. and was stirred 7 hours to eflfect polymerization. Thepolymer was isolated by precipitation with water, and dried. A yield of35 lbs. was obtained. 10 grams of the polymer was dissolved in g. of 0.1N HCl and the pH was adjusted to 4.5 with dilute sodium hydroxide. Tothe solution was added 3.5 g. of a mixture of lipolytic and proteaseenzymes, and the solution was dried at 25 C. in vacuo to provide a filmhaving the enzymes trapped therein.

The film was ground and dry dispersed in an amount of 10% in acommercial detergent composition, specifically Fab, a mixture of 14 to18 carbon atom alkyl alcohols, 10-18 carbon atom linear alkanesulfonates, plotassium xylene sulfonate and tetra potassium pyrophospate.

0n aging it was noted that enzyme activity was maintained at a highlevel when the detergent containing the entrapped enzymes was added towater. Thus, entrapping the enzymes in the polymer film serves toprotect them from degradation during storage by the alkalinity of thedetergent composition.

EXAMPLE 11 Example 2 was repeated replacing the orange oil by artificialstrawberry flavor. 10 parts of the strawberry flavor containing powderwas blended with 10 parts of sugar, 3 parts of citric acid and 4 partsof sodium bicarbonate to produce a powder which when added to waterdissolved to form a sparkling clear, carbonated strawberry flavoredbeverage.

EXAMPLE 12 The procedure of Example 11 was repeated replacing thestrawberry flavor by (a) an equal weight of lemon- ]ime flavor toproduce a lemon-lime beverage and (b) by an equal weight of syntheticcherry flavor to produce a cherry flavor.

9 EXAMPLE 13 The procedure of Example 2 was repeated replacing theorange oil by an equal weight of vanillin. The resulting vanillinflavored powder was used in the preparation of dry cake mixes.

EXAMPLE 14 The procedure of Example 2 was repeated using an equal weightof biacetyl in place of the orange oil to produce a powder providingflavor enhancement when used in dry cake mixes and in oleomargarine.

EXAMPLE 15 The polymer of Example 8 was dissolved in methanol to form a7 weight percent solution. The solution was divided into 3 portions. Toportion No. 1 was added a pine fragrance at a level of 10% of thepolymer content. To portion No. 2 at the same level there was added anew mown hay fragrance and to portion No. 3 a lilac fragrance was addedat the same level. The three solutions were then spray-dried to providepowders containing the respective fragrances. These powders weresuitable for incorporation into soap cakes in the manner described inExample 5 and at a level of 1 pound of entrapped fragrance powder topounds of soap powder. Soap thus treated when extruded and stamped intocakes retained the fragrance for the life of the soap.

EXAMPLE 16 EXAMPLE 17 The polymer of Example 1 was dissolved in a 50:50methanol/water mixture to provide a solution containing solids. In 100g. of the solution was dissolved 5 g. of sodium acetyl salicylate(aspirin). The solution was dried as a thin film on a rotatingevaporator and the dried film was granulated. The powder was pelletizedinto 250 mg. tablets with a tableting press. The tablets, containing62.5 mg. of aspirin swelled, but did not dissolve in 0.1 N HClsolutions, but were soluble at a pH above 5.5 such as is encountered inthe intestinal tract.

EXAMPLE 18 Example 17 was repeated using the polymer of Example 10. Theresulting tablets containing aspirin were soluble in the acidicenvironment of the stomach, but only swelled slightly in water at a pHabove 5 .5

EXAMPLE 19 Example 17 was repeated using amorbarbitol sodium in place ofaspirin. Equivalent results were obtained.

EXAMPLE 20 Example 17 was repeated using prednisone, an antiinfiammatoryagent. Equivalent results were obtained.

EXAMPLE 21 The polymer of Example 1 was dissolved in ethanol to providea solution containing 15% solids. In 100 grams of 10 the solution weredissolved 3 grams of penicillin and the solution dried as a thin filmand treated as in Example 20 to produce tablets containing thepenicillin and polymer.

EXAMPLE 22 The polymer of Example 10 was dissolved in ethanol to providea solution containing 10% solids. In grams of the solution was dissolved1 gram of 2,4-dicl1lorophenoxy acetic acid and the solution dried as athin film and granulated. The granulated powder was suitable as a sourceof the herbicide.

EXAMPLE 23 The polymer of Example 10 was dissolved in ethanol to providea solution containing 15 solids. In 100 grams of the solution wasdissolved 4 grams of parathion and the solution dried as a film andgranulated, The granulated powder was suitable for use in applyingparathion to plants and to the soil.

EXAMPLE 24 The procedure of Example 23 was repeated replacing theparathion by phenyl mercuric acetate to provide a fungicidal dry powder.

EXAMPLE 25 The water soluble polymers are also useful to entrapvitamins. Thus, there can be entrapped thiamine, riboflavin,nicotinamide, pantothenic acid, pyridoxine, biotin, inositol,p-aminobenzoic acid, cyanocobalamin, ascorbic acid, Vitamins K K P and Kalcohol soluble vitamins such as Vitamin A, Vitamins D D and D andVitamin B.

To 100 grams of a 10% solution of the polymer prepared in Example 10 inwater there was added Zgrams of riboflavin phosphate. The solution wasdried as a film and granulated. The product was readily soluble in waterand provided a source of Vitamin B In place of riboflavin in thisexample there can also be used the same amount of ascorbic acid ornicotinamide to provide a stable water soluble source thereof.

As used in the claims the term drugs is intended to include vitamins.

The materials entrapped in the water soluble hydroxyalkyl, acrylate ormethacrylate polymer can be either solids or liquids and numerousexamples of both solids and liquids are set forth supra.

As used in the claims the term detergent is intended to include soaps.

What is claimed is:

1. A powdered dry composition drug adapted to be orally digestedconsisting essentially of a solid, hydrophilic, water soluble copolymerof a member of the group consisting of hydroxyethyl acrylate,hydroxypropyl acrylate, hydroxyethyl methacrylate and hydroxypropylmethacrylate with 0.5 to 20% of a water solubilizing copolymerizablemonomer selected from the group consisting of 1) alkali metal andammonium salts of polymerizable organic acids imparting solubility at apH above about 3.5 and (2) strong acid salts of polymerizable organicamines imparting solubility at a pH below about 8.5, said Watersolubilizing monomer units being present in the copolymer in sufficientamounts to render the copolymer completely soluble in water, havingentrapped therein 01 to 35%, based on the weight of the polymer of asolid or liquid organic drug, said composition being adapted to releasethe entrapped drug ingested by pH dependent solubility of the polymer atpH levels encountered upon oral ingestion upon contact with water byvirtue of the dissolution of the water soluble polymer in water, saidpolymer composition protecting the entrapped drug from atmosphericoxygen and preventing diffusion and loss thereof, said composition beingformed from a substantially anhydrous casting syrup of the entrappeddrug and the monomers and polymerizing the composition.

2. A composition according to claim 1 wherein said R f es Citedcopolymerizable monomer is ethylenically unsaturated. UNITED STATESPATENTS 3. A composition according to claim 2 wherein the acrylate ormethacrylate is hydroxyethyl methacrylate and 3,576,760 4/1971 GQUId et252.403 said copolymerizable monomer is the salt of a polymer- 5 332096011/1965 Wlchterle et aL 260-25 izable organic acid.

4. A composition according to claim 2 wherein the acry- SHEP ROSE PnmaryExaminer late or methacrylate is hydroxyethyl methacrylate and Us Cl XRsaid copolymerizable monomer is a salt of an organic amine. 10 424-230,243, 252, 254, 271

